ABSTRACT
The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors.
ABSTRACT
The long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of IIIM-019. The solubility profile of IIIM-019 using various polymeric carriers was determined and subsequently, PVP K-30 and P-407 were selected for preparation of binary and ternary solid dispersion. The third-generation ternary solid dispersion comprising PVP K-30 and P-407 revealed a remarkable enhancement in the aqueous solubility of IIIM-019. Physicochemical characterization of the developed formulations was done by employing FTIR spectroscopy, scanning electron microscopy, X-ray diffraction analysis, differential scanning calorimetry, and dynamic light scattering analysis. The dissolution study indicated an impressive release profile with the optimized formulation. The optimized formulation was further examined for cytotoxicity, cellular uptake, and hemolytic activity. The results indicated that the formulation had no apparent cytotoxicity on Caco-2 cells and was non-hemolytic in nature. Moreover, the optimized formulation showed significantly improved anti-tubercular activity compared to the native molecule. These findings showed that the developed third generation ternary solid dispersion could be a promising option for the oral delivery of investigated anti-tubercular molecule.
Subject(s)
Antitubercular Agents , Solubility , Antitubercular Agents/administration & dosage , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Humans , Drug Carriers/chemistry , Mycobacterium tuberculosis/drug effects , Drug Liberation , Caco-2 Cells , Drug Compounding/methods , Chemistry, Pharmaceutical/methodsABSTRACT
Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.
Subject(s)
Diarylquinolines , Drug-Related Side Effects and Adverse Reactions , Mycobacterium tuberculosis , Nitroimidazoles , Tuberculosis, Multidrug-Resistant , Humans , Antitubercular Agents/adverse effects , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology , Nitroimidazoles/pharmacology , Nitroimidazoles/therapeutic use , Oxazoles/pharmacology , Oxazoles/therapeutic use , Drug ResistanceABSTRACT
Identification of structurally unique chemical entities targeting unexplored bacterial targets is a prerequisite to combat increasing drug resistance against Mycobacterium tuberculosis. This study employed a whole-cell screening approach as an initial filter to scrutinize a 10,000-compound chemical library, resulting in the discovery of seven potent compounds with MIC values ranging from 1.56 to 25 µM. These compounds were categorized into four distinct chemical groups. Remarkably, they demonstrated efficacy against drug-resistant and nonreplicating tuberculosis strains, highlighting their effectiveness across different infection states. With a favorable selectivity index (>10), these compounds showed a safe therapeutic range and exhibited potency in an intracellular model of Mtb infection, mimicking the in vivo setup. Combining these identified hits with established anti-TB drugs revealed additive effects with rifampicin, isoniazid, and bedaquiline. Notably, IIIM-IDD-01 exhibited synergy with isoniazid and bedaquiline, likely due to their complementary mechanisms of targeting Mtb. Most potent hits, IIIM-IDD-01 and IIIM-IDD-02, displayed time- and concentration-dependent killing of Mtb. Mechanistic insights were sought through SEM and docking studies, although comprehensive evaluation is ongoing to unravel the hits' specific targets and modes of action. The hits demonstrated favorable pharmacokinetic properties (ADME-Tox) and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. These promising hits can serve as an initial basis for subsequent medicinal chemistry endeavors aimed at developing a new series of anti-TB agents. Moreover, the study affirms the significance of high-throughput in vitro assays for the TB drug discovery. It also emphasizes the necessity of targeting diverse TB strains to address the heterogeneity of tuberculosis bacteria.
Subject(s)
Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis , Humans , Antitubercular Agents/chemistry , Isoniazid/pharmacology , Microbial Sensitivity Tests , Tuberculosis/microbiologyABSTRACT
Tuberculosis has remained a global concern for public health affecting the lives of people for ages. Approximately 10 million people are affected by the disease and 1.5 million succumb to the disease worldwide annually. The COVID-19 pandemic has highlighted the role of early diagnosis to win the battle against such infectious diseases. Thus, advancement in the diagnostic approaches to provide early detection forms the foundation to eradicate and manage contagious diseases like tuberculosis. The conventional diagnostic strategies include microscopic examination, chest X-ray and tuberculin skin test. The limitations associated with sensitivity and specificity of these tests demands for exploring new techniques like probe-based assays, CRISPR-Cas and microRNA detection. The aim of the current review is to envisage the correlation between both the conventional and the newer approaches to enhance the specificity and sensitivity. A significant emphasis has been placed upon nanodiagnostic approaches manipulating quantum dots, magnetic nanoparticles, and biosensors for accurate diagnosis of latent, active and drug-resistant TB. Additionally, we would like to ponder upon a reliable method that is cost-effective, reproducible, require minimal infrastructure and provide point-of-care to the patients.
Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Humans , Mycobacterium tuberculosis/genetics , Pandemics , COVID-19/diagnosis , Tuberculosis/diagnosis , Tuberculin Test/methodsABSTRACT
The SARS-CoV-2 pandemic has claimed around 6.4 million lives worldwide. The disease symptoms range from mild flu-like infection to life-threatening complications. The widespread infection demands rapid, simple, and accurate diagnosis. Currently used methods include molecular biology-based approaches that consist of conventional amplification by RT-PCR, isothermal amplification-based techniques such as RT-LAMP, and gene editing tools like CRISPR-Cas. Other methods include immunological detection including ELISA, lateral flow immunoassay, chemiluminescence, etc. Radiological-based approaches are also being used. Despite good analytical performance of these current methods, there is an unmet need for less costly and simpler tests that may be performed at point of care. Accordingly, nanomaterial-based testing has been extensively pursued. In this review, we discuss the currently used diagnostic techniques for SARS-CoV-2, their usefulness, and limitations. In addition, nanoparticle-based approaches have been highlighted as another potential means of detection. The review provides a deep insight into the current diagnostic methods and future trends to combat this deadly menace.
Subject(s)
COVID-19 , Nanoparticles , Humans , COVID-19/diagnosis , SARS-CoV-2/genetics , COVID-19 Testing , Sensitivity and Specificity , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/methods , RNA, Viral/geneticsABSTRACT
Tuberculosis (TB) is an infectious disease, infecting a quarter of world's population. Drug resistant TB further exacerbates the grim scenario of the drying TB drug discovery pipeline. The limited arsenal to fight TB presses the need for thorough efforts for identifying promising hits to combat the disease. The review highlights the efforts in the field of tuberculosis drug discovery, with an emphasis on massive drug screening campaigns for identifying novel hits against Mtb in both industry and academia. As an intracellular pathogen, mycobacteria reside in a complicated intracellular environment with multiple factors at play. Here, we outline various strategies employed in an effort to mimic the intracellular milieu for bringing the screening models closer to the actual settings. The review also focuses on the novel targets and pathways that could aid in target-based drug discovery in TB. The recent high throughput screening efforts resulting in the identification of potent hits against Mtb has been summarized in this article. There is a pressing need for effective screening strategies and approaches employing innovative tools and recent technologies; including nanotechnology, gene-editing tools such as CRISPR-cas system, host-directed bacterial killing and high content screening to augment the TB drug discovery pipeline with safer and shorter drug regimens.
Subject(s)
Antitubercular Agents/administration & dosage , Drug Delivery Systems/methods , Drug Discovery/methods , High-Throughput Screening Assays/methods , Tuberculosis/drug therapy , Animals , Antitubercular Agents/metabolism , Energy Metabolism/drug effects , Energy Metabolism/physiology , Humans , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/metabolism , Tuberculosis/metabolismABSTRACT
The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.
Subject(s)
Antitubercular Agents/chemistry , Extensively Drug-Resistant Tuberculosis/drug therapy , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Antitubercular Agents/pharmacokinetics , Diarylquinolines/pharmacology , Diarylquinolines/standards , Drug Therapy, Combination , Ethambutol/chemistry , Ethambutol/pharmacology , Humans , Isoniazid/chemistry , Isoniazid/pharmacology , Nitroimidazoles/pharmacology , Nitroimidazoles/standards , Oxazoles/pharmacology , Oxazoles/standards , Pyrazinamide/chemistry , Pyrazinamide/pharmacology , Rifampin/chemistry , Rifampin/pharmacologyABSTRACT
Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The primary causative agents of the disease comprise of diverse leishmanial species sharing clinical features ranging from skin abrasions to lethal infection in the visceral organs. As several Leishmania species are involved in infection, the role of accurate diagnosis becomes pivotal in adding new dimensions to anti-leishmanial therapy. Diagnostic methods must be fast, reliable, easy to perform, highly sensitive, and specific to differentiate among similar parasitic diseases. Herein, we present the conventional and recent approaches impended for the disease diagnosis and their sensitivity, specificity, and clinical application in parasite detection. Furthermore, we have also elaborated various new methods to cure leishmaniasis, which include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy. This review addresses novel techniques and innovations in leishmaniasis, which can aid in unraveling new strategies to fight against the deadly infection.